In the United States, the lifetime risk for the development of hypertension is >80% and one in three adults will develop hypertension and require antihypertensive therapy. Only 50% of patients with hypertension attain adequate blood pressure control with current antihypertensive drugs. The reasons why hypertension is so difficult to control especially in elderly patients remain incompletely understood. There is evidence that regardless of the causes of the hypertension, the development and maintenance of hypertension are dependent upon the resetting of the pressure natriuresis relationship to higher pressures. However, the key factors and mechanisms responsible for resetting pressure natriuresis responses in hypertension remain unknown. We have recently shown that angiotensin II (ANG II) significantly increased the expression and/or activity of the sodium and hydrogen exchanger 3 (NHE3) in the proximal tubule of rats and mice via AT1a receptors. Further, we have powerful preliminary data that proximal tubule-selective deletion of NHE3 or AT1a receptors with the Cre/Lox approach markedly inhibits proximal tubule Na+ reabsorption, promotes pressure natriuresis, and attenuates blood pressure responses in ANG II-dependent hypertensive mice. In this proposal, we will test the hypothesis that increased Na+ reabsorption due to overexpression or upregulation of NHE3 selectively in the proximal tubule of the kidney in response to inappropriately elevated paracrine and intracellular ANG II contributes to the resetting of pressure natriuresis responses to higher pressures, and the development of hypertension. Further, we test the hypothesis that proximal tubule-selective deletion or inhibition of NHE3 will promote pressure natriuresis responses and attenuate genetic and ANG II-dependent hypertension. Three specific aims are proposed to test these hypotheses. In Specific Aim 1, we will determine whether the overexpression of NHE3 selectively in the proximal tubule will stimulate proximal tubule Na+ reabsorption, reset pressure natriuresis to higher pressure, and increase blood pressure, whereas deletion of NHE3 selectively in the proximal tubule will inhibit proximal tubule Na+ reabsorption, promote pressure natriuresis, and decrease blood pressure using proximal tubule-specific NHE3-KO mice. In Specific Aim 2, we will determine a subpressor dose of ANG II and a 2% Na+ diet will promote proximal tubule Na+ reabsorption, resets pressure natriuresis, and induces hypertension by increasing the expression of NHE3 in the proximal tubule, whereas deletion of NHE3 or AT1a receptors selectively in the proximal tubule will attenuate ANG II- dependent hypertension. In Specific Aim 3, we will determine whether an orally active, absorbable, specific NHE3 inhibitor to selectively inhibit NHE3 in the proximal tubule of the kidney will prevent the development of hypertension in young SHR and lower blood pressure in a subpressor ANG II-induced hypertensive mouse model. The successful outcome of this proposal will help develop novel proximal tubule-specific NHE3 inhibitors to treat patients with poorly-controlled hypertension.